Roughly 100 years ago William Bateson coined the term epistasis, which is today generally considered as a form of interaction between two loci in DNA. Research in epistasis has over the years revealed fascinating biological insights, however, until very recently, progress has been slowed by limited availability of densely sampled population data. Given the advent of latest sequencing technology we are finally facing possibility to query what experiments nature has performed concerning epistasis. I will present latest research results from a close collaboration with the Pathogen Genomics group at WTSI on how we can advance understanding about epistasis in genomes by exploiting core concepts from statistical physics and statistical machine learning algorithms for ultra-high dimensional models. Our genome-wide epistasis analysis reveals interacting networks of resistance, virulence and core machinery genes in Streptococcus pneumoniae.